Deleted in liver cancer protein family in human malignancies (Review)

Łukasik, Dominika; Wilczek, Ewa; Wasiutyński, Aleksander; Górnicka, Barbara

doi:10.3892/ol.2011.345

Cited by 20 publications

(22 citation statements)

References 64 publications

(111 reference statements)

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“…In fact, there are also contradictory results regarding the role of a closely related protein, DLC1, in cell migration. DLC1 is a well-established tumor suppressor that has been shown to inhibit proliferation, induce apoptosis, and suppress migration [32]. However, at least two reports show that DLC1 positively regulates cell migration similar to our data with DLC2.…”

Section: Discussionsupporting

confidence: 89%

The regulation of RhoA at focal adhesions by StarD13 is important for astrocytoma cell motility

Khalil

Hanna

Saykali

et al. 2014

Experimental Cell Research

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Malignant astrocytomas are highly invasive into adjacent and distant regions of the normal brain. Rho GTPases are small monomeric G proteins that play important roles in cytoskeleton rearrangement, cell motility, and tumor invasion. In the present study, we show that the knock down of StarD13, a GTPase activating protein (GAP) for RhoA and Cdc42, inhibits astrocytoma cell migration through modulating focal adhesion dynamics and cell adhesion. This effect is mediated by the resulting constitutive activation of RhoA and the subsequent indirect inhibition of Rac. Using Total Internal Reflection Fluorescence (TIRF)-based Förster Resonance Energy Transfer (FRET), we show that RhoA activity localizes with focal adhesions at the basal surface of astrocytoma cells. Moreover, the knock down of StarD13 inhibits the cycling of RhoA activation at the rear edge of cells, which makes them defective in retracting their tail. This study highlights the importance of the regulation of RhoA activity in focal adhesions of astrocytoma cells and establishes StarD13 as a GAP playing a major role in this process.

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Section: Discussionsupporting

confidence: 89%

The regulation of RhoA at focal adhesions by StarD13 is important for astrocytoma cell motility

Khalil

Hanna

Saykali

et al. 2014

Experimental Cell Research

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“…While certain RhoGAPs, most notably DLC1 (14,15), have been characterized and well-validated as tumor suppressors, our findings indicate that this classification is not applicable to all members of the RhoGAP family, as had previously been assumed. Compared to RhoGEFs, RhoGAPs are relatively poorly characterized, particularly with regard to their role in cancer.…”

Section: Discussionmentioning

confidence: 57%

“…In contrast, RhoGAPs, which stimulate the intrinsic GTPase activity of Rho proteins and return them to an inactive, GDP-bound state (12), are generally presumed to inhibit tumorigenesis (13). For example, the RhoGAP DLC1 is commonly lost in cancer through promoter methylation, genomic deletion, or enhanced protein degradation (14,15). Hence, the prevailing dogma in the field is that Rho GTPases and RhoGEFs are oncogenes in cancer, whereas RhoGAPs are tumor suppressors.…”

Section: Introductionmentioning

confidence: 99%

Rho GTPase Transcriptome Analysis Reveals Oncogenic Roles for Rho GTPase-Activating Proteins in Basal-like Breast Cancers

et al. 2016

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The basal-like breast cancer (BLBC) subtype accounts for a disproportionately high percentage of overall breast cancer mortality. The current therapeutic options for BLBC need improvement; hence, elucidating signaling pathways that drive BLBC growth may identify novel targets for the development of effective therapies. Rho GTPases have previously been implicated in promoting tumor cell proliferation and metastasis. These proteins are inactivated by Rho-selective GTPase-activating proteins (RhoGAPs), which have generally been presumed to act as tumor suppressors. Surprisingly, RNA-Seq analysis of the Rho GTPase signaling transcriptome revealed high expression of several RhoGAP genes in BLBC tumors, raising the possibility that these genes may be oncogenic. To evaluate this, we examined the roles of two of these RhoGAPs, ArhGAP11A (also known as MP-GAP) and RacGAP1 (also known as MgcRacGAP), in promoting BLBC. Both proteins were highly expressed in human BLBC cell lines, and knockdown of either gene resulted in significant defects in the proliferation of these cells. Knockdown of ArhGAP11A caused CDKN1B/p27-mediated arrest in the G1 phase of the cell cycle, whereas depletion of RacGAP1 inhibited growth through the combined effects of cytokinesis failure, CDKN1A/p21-mediated RB1 inhibition, and the onset of senescence. Random migration was suppressed or enhanced by the knockdown of ArhGAP11A or RacGAP1, respectively. Cell spreading and levels of GTP-bound RhoA were increased upon depletion of either GAP. We have established that, via the suppression of RhoA, ArhGAP11A and RacGAP1 are both critical drivers of BLBC growth, and propose that RhoGAPs can act as oncogenes in cancer.

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“…These include solid tumors, such as liver cancer, lung cancer, colorectal cancer, prostate cancer, and breast cancer, as well as several hematopoietic neoplasms [12, 13]. DLC1 was the first family member identified, and a considerable amount of clinical and experimental evidence has established it as a bona fide tumor suppressor gene.…”

Section: Introductionmentioning

confidence: 99%

“…DLC1 was the first family member identified, and a considerable amount of clinical and experimental evidence has established it as a bona fide tumor suppressor gene. Overexpression of DLC1 inhibits several biological parameters of neoplastic growth [13], and inactivation of endogenous DLC1 can, in conjunction with other genetic and/or epigenetic changes, lead to cell transformation and tumor formation [14, 15]. DLC2 and DLC3 have been studied less extensively, but they also appear to be tumor suppressors that are down-regulated in malignancies [9, 16].…”

Section: Introductionmentioning

confidence: 99%

DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers

et al. 2016

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The RHO family of RAS-related GTPases in tumors may be activated by reduced levels of RHO GTPase accelerating proteins (GAPs). One common mechanism is decreased expression of one or more members of the Deleted in Liver Cancer (DLC) family of Rho-GAPs, which comprises three closely related genes (DLC1, DLC2, and DLC3) that are down-regulated in a wide range of malignancies. Here we have studied their comparative biological activity in cultured cells and used publicly available datasets to examine their mRNA expression patterns in normal and cancer tissues, and to explore their relationship to cancer phenotypes and survival outcomes. In The Cancer Genome Atlas (TCGA) database, DLC1 expression predominated in normal lung, breast, and liver, but not in colorectum. Conversely, reduced DLC1 expression predominated in lung squamous cell carcinoma (LSC), lung adenocarcinoma (LAD), breast cancer, and hepatocellular carcinoma (HCC), but not in colorectal cancer. Reduced DLC1 expression was frequently associated with promoter methylation in LSC and LAD, while DLC1 copy number loss was frequent in HCC. DLC1 expression was higher in TCGA LAD patients who remained cancer-free, while low DLC1 had a poorer prognosis than low DLC2 or low DLC3 in a more completely annotated database. The poorest prognosis was associated with low expression of both DLC1 and DLC2 (P < 0.0001). In cultured cells, the three genes induced a similar reduction of Rho-GTP and cell migration. We conclude that DLC1 is the predominant family member expressed in several normal tissues, and its expression is preferentially reduced in common cancers at these sites.

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Deleted in liver cancer protein family in human malignancies (Review)

Cited by 20 publications

References 64 publications

The regulation of RhoA at focal adhesions by StarD13 is important for astrocytoma cell motility

The regulation of RhoA at focal adhesions by StarD13 is important for astrocytoma cell motility

Rho GTPase Transcriptome Analysis Reveals Oncogenic Roles for Rho GTPase-Activating Proteins in Basal-like Breast Cancers

DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers

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